In 2015, more than 300 million people experienced major depressive disorder (MDD) [1]. This number has increased in recent years, partly due to COVID-19 [2]. Furthermore, in the Global Burden of Disease study of 2023, depressive disorders were in the top 3 causes of years lived with disability [3]. Common treatment options for MDD include psychological and pharmacological interventions. However, approximately 30% to 55% of patients with MDD receiving treatment have treatment-resistant depression (TRD) and, thus, do not meet remission criteria [4,5]. In addition to treatment resistance, recurrence and relapse pose another challenge. Experiencing a depressive episode increases vulnerability to relapse (40%-90% of individuals with a depressive episode relapse), and this vulnerability only increases after multiple episodes of depression [6]. Research has shown that fluctuations in positive and negative affect, especially reductions in positive affect, can predict depressive symptomatology up to 6 months after remission [7]. Notably, the 1-item visual analog mood scale outperformed the widely used 17-item Hamilton Depression Rating Scale (HDRS-17) or Inventory of Depressive Symptomatology–Self-Report (IDS-SR) in predicting relapse over 2 years [8]. This suggests that measuring affect fluctuations using experience sampling methodology (ESM) may be useful in predicting relapse after remission and may help assess the effectiveness of relapse prevention strategies.

In recent years, neurobiological treatments have emerged as a treatment option for MDD in general. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique in which electrical currents are induced to change cortical excitability using rapidly changing electromagnetic fields [9,10]. In the Netherlands, rTMS is offered as a first-line treatment for individuals with MDD who have not responded to at least two other treatments [11]. An electromagnetic coil is used to induce focal currents that stimulate cortical brain regions. The coil is placed on the left and/or right dorsolateral prefrontal cortex when treating MDD [12]. The dorsolateral prefrontal cortex plays a part in emotion regulation [13]. As rTMS can alter synaptic plasticity by changing long-term potentiation (ie, high-frequency rTMS) and long-term depression (ie, low-frequency rTMS) of synaptic transmission, it can target the found frontal hypoactivity in MDD. This frontal hypoactivity causes apathy and decreased executive functioning [14-17]. The response rate of rTMS in patients with MDD has been found to be approximately 40% to 66% depending on concomitant psychotherapy, such as cognitive behavioral therapy (CBT) [14,18]. In recent years, rTMS has proven to be an effective treatment for TRD [18,19]. Since 2017, rTMS has been included in the reimbursement policies of health care insurance in the Netherlands. Subsequently, since 2024, rTMS has been incorporated into the Dutch depression guideline as a treatment option for TRD combined with CBT [11,20]. However, data on long-term effects and management after rTMS are sparse, and a large amount of treated patients experience relapse. For example, in one study, only 60% of rTMS responders maintained remission at 3 months, and just 22.6% remained in remission at 6 months after treatment [21].

Combining neurobiological and psychological interventions in a multimodal treatment approach is more effective than offering these interventions separately, as shown in previous research. For example, adding a psychological intervention after successful antidepressant treatment has proven to reduce relapse and recurrence rates [22,23]. In rTMS, high relapse rates may be altered by adding psychotherapeutic interventions, as is the case in pharmacological approaches. Earlier studies have shown that combining rTMS treatment with CBT in depression leads to enhanced treatment outcomes [11,24,25]. However, it has not yet been studied whether psychotherapy can sustain the antidepressant effects of this neurobiological treatment. Adding psychological interventions after successful rTMS treatment may lead to a reduction in MDD relapse and recurrence.

Currently, there are no standardized treatment options available to maintain remission after rTMS treatment and prevent relapse. However, some studies have investigated maintenance rTMS and found better effects in comparison to antidepressant monotherapy [24] and sham rTMS [25]. As a review indicates, patients prefer psychotherapy over antidepressant medication as a form of relapse prevention [26]. Therefore, it is important to investigate psychotherapeutic interventions as a means to potentially sustain the benefits of rTMS treatment. A recent meta-analysis found that preventive cognitive therapy (PCT) can reduce depressive symptoms in partially recovered patients when applied immediately after psychological treatment, as well as reducing relapse risk over 12 months [27-29]. Even patients more at risk at baseline were found to benefit from these interventions [27]. Thus, these strategies may also be effective as a relapse prevention strategy after successful rTMS.

Research has shown that the meta-plasticity caused by rTMS treatment improves response to subsequent psychological treatment [30,31]. This creates an optimal opportunity for preventive therapies such as PCT to reduce relapse rates following rTMS treatment. PCT consists of the following three elements [28,29]: (1) identifying dysfunctional beliefs and schemas using specific cognitive challenging techniques that elicit positive fantasy, (2) enhancing and recalling specific autobiographical memories of positive experiences, and (3) creating a personalized prevention plan [28,29,32]. PCT has been studied in several randomized controlled trials (RCTs) and has shown to have protective effects against relapse up to 20 years after administration [22,33-37]. Substantial effects have been found particularly in those who have a high risk of relapse, that is, clients with recurrent MDD or who have remitted partially. When PCT was combined with antidepressant medication in remitted clients with depression with a recurrent profile, the risk of relapse was reduced considerably (41% risk reduction over 2 years) [22]. In addition, PCT has been established as an alternative treatment by replacing long-term (maintenance) use of antidepressants [22]. In one study, after 20 years, the interval between MDD episodes in individuals was significantly longer after PCT, and these participants had 54% less recurrence of episodes when compared to those who underwent treatment as usual [35]. PCT started after partial and full remission has proven to have preventive effects for patients even after receiving other psychological treatment [6,27,33,34,38-43]. To be eligible for rTMS treatment, patients usually have to have a long treatment history, including different pharmaceutical treatments and CBT, without substantial response [44]. Therefore, PCT seems to be suitable to administer to patients who have received rTMS due to its demonstrated effect in partial remission and the effectiveness after other treatment options [44,45]. As PCT and rTMS target similar patient groups and the meta-plasticity induced by rTMS enhances treatment response, this creates a unique opportunity to prolong the effects of rTMS in remitted patients. Normally, when remission of MDD is reached, PCT is provided 10 weeks after being in remission at the earliest [33,46]. However, we suspect that, if PCT is provided immediately at the end of rTMS treatment to (partial) responders, patients will be more likely to maintain and prolong their remission period due to the meta-plastic benefits directly after rTMS [21].

A major concern of combining PCT with rTMS is the intensity of treatment. rTMS is usually provided daily during several weeks before producing effects. Moreover, some patients finally experience effects after a long treatment history. Therefore, adding 8 weekly sessions to this intensive treatment period may be experienced as a burden. We will study the feasibility of combining PCT with rTMS either face-to-face or online, and treatment adherence will be measured to determine the best treatment delivery for these patients. Previous research has shown that online CBT is as effective as face-to-face treatment [47-49]. Brouwer et al [41] have indicated that online-delivered PCT is also effective. However, online PCT may be viewed as less pleasant due to the lack of personal contact with the therapist, whereas face-to-face delivery may constitute an additional burden after intensive treatment.

On the basis of these previous studies, the primary objective of this pilot study is to compare feasibility and adherence to treatment between online and face-to-face PCT to minimize dropout in a larger RCT. Secondary objectives are to explore the effects of offering PCT to patients who (partially) responded to rTMS treatment on affect fluctuations and remission periods, and study the potential benefits of these measurements for a larger trial.

This study is a pragmatic monocenter RCT with a 1:1 parallel-group design. Twenty patients with MDD who (partially) responded to rTMS treatment will be randomized to either face-to-face or online PCT. This sample size was selected based on practical feasibility in terms of the number of patients with MDD receiving rTMS treatment in Amsterdam, the Netherlands. PCT will be offered as soon as possible after the last rTMS session. Throughout the course of PCT, all patients in both conditions will receive 8 weekly individual sessions (either online or in person) and will be asked to fill out a daily short-form questionnaire. Patients will be assessed before PCT (baseline), directly after PCT (after treatment), and 3 and 6 months after baseline. Total participation duration for the study will be approximately 6 months, as shown in Figure 1. Table 1 provides an overview of the study assessments.

Patients will be recruited at the outpatient clinic of Amsterdam University Medical Center (UMC; location Academic Medical Center). Other rTMS treatment facilities in Amsterdam can refer potential participants to the study if they meet the inclusion criteria of (partially) responding to rTMS treatment. Data collection will take place at Amsterdam UMC in person or via phone or video call based on the preference of the participant mentioned at previous assessments. Preference will be recorded.

Eligible patients must be aged at least 18 years and have (partially) responded to rTMS treatment. We define response or remission as having an IDS-SR score of 14 or lower or a 50% reduction in IDS-SR score. Partial response is determined by an IDS-SR score between 14 and 22 or a reduction between 25% and 50% in IDS-SR score. Patients need to be able to speak and understand Dutch. There are no predefined exclusion criteria as only a select number of patients are found eligible for rTMS.

Patients interested in the study may contact the study researchers directly or give consent to their health care providers to forward their contact details to the researchers. Eligibility screening will be conducted by treating psychiatrists, therapists, or health care providers. Patients will be deemed eligible if they show at least partial response on the IDS-SR (ie, score lower than 22). Prior to participation, potential participants will be provided with detailed information about the study and given 3 days to consider their consent, as requested by the Medical Research Ethics Committee (MREC). Written informed consent will be obtained prior to enrollment and participation in the baseline assessment. The baseline assessment will consist of both clinician-rated and self-report questionnaires. If the participant completes the HDRS-17 and IDS-SR for rTMS treatment within 2 weeks before the baseline assessment, the scores obtained will be used for the baseline assessment instead of administering the IDS-SR and HDRS-17 during this study visit. When the baseline assessment is completed, randomization will take place using a randomization tool in Castor. All participants in the study will be insured by the facility in case of adverse events connected to study participation.

All participants will receive 8 weekly individual PCT sessions with a duration of 45 minutes each administered by a trained licensed therapist from Amsterdam UMC. PCT is based on the model by Beck [51] and specifically designed for relapse prevention [28,29,42]. Each session consists of a structured format, starting with homework review and explanation of the sessions’ rationale and ending with homework assignments. Homework is an essential part of the therapy and will take 10 minutes each day at most. The treatment is based on the PCT manual [27-29,32].

The number of attended sessions, the overall time taken by the sessions, and whether homework was done will be monitored. All concomitant care will be allowed during the intervention, but if patients are no longer in remission during treatment, they will be noted as relapsed and withdrawn from the study and then referred to their treating psychiatrists for further treatment options. The date of relapse will be noted and used in the analysis of our secondary outcomes.

In total, 20 participants will be randomized with a 1:1 allocation ratio to PCT online or face-to-face. A computer-generated randomization table with small block sizes stratified by gender will be used by an independent researcher. After randomization has taken place, an independent researcher (who is not blinded to treatment allocation and will not conduct outcome assessments) will contact the participants and related health care professionals to communicate the participants’ treatment allocation to start the PCT sessions. Participants will be instructed not to share treatment allocation with the blinded outcome assessor. This is to ensure that outcome assessors remain blinded until the end of data collection and consequent database lock.

If knowledge of the allocated group is necessary for the safety of the patients or providing medical treatment, unblinding will be performed by the treating psychologist or the previously mentioned independent researcher.

All randomized participants will be included in the analysis and assessed by intervention group.

All study and medical data will be handled confidentially in accordance with the European Union (EU) General Data Protection Regulation and the Dutch General Data Protection Regulation Implementation Act. All participant data will be securely stored using a coded participant ID number. Informed consent forms will be stored separately from the participant ID-coded study records (eg, the clinician-rated HDRS-17 forms) in a locked file cabinet to which limited access is guaranteed. Only staff members (eg, clinical interns and clerical personnel) authorized by the principal investigators, the monitoring agency of Amsterdam UMC, and the Health and Youth Care Inspectorate will be allowed access to the original documents. All electronic databases are password protected and stored securely on a local Amsterdam UMC drive. Data collection will mostly take place via direct entry into Castor Electronic Data Capture. The videoconferencing program that will be used is built into Epic (ie, telehealth) and thereby creates a secure line directly to the participants. No digital information on the PCT sessions will be stored (ie, sessions will not be recorded), and it will be ascertained that the correct videoconferencing program is used for communication between participants and therapists. This will ensure participants’ privacy during online treatment.

Data will be stored for 15 years within Amsterdam UMC in accordance with Dutch guidelines.

Coded data may be used for other research on rTMS and/or PCT. Participants need to provide informed consent prior to the use of their data in other research (as an opt-in item on the informed consent form). Storage for 15 years will be applied. Coded data will be shared with other sites on reasonable request for noncommercial research purposes. Coded data could be sent to countries outside of the EU where other privacy regulations are in place. Non-EU countries will only receive coded data preserving participant privacy to the best of our ability. If data are shared, they will be fully coded in accordance with Dutch privacy regulations.